A new, efficient and recyclable [Ce(l-Pro)]2(Oxa) heterogeneous catalyst used in the Kabachnik-Fields reaction

Article abstract of DOI:10.1039/c5ra27064b

Herein we introduce a new catalyst for the Kabachnik-Fields reaction, [Ce(l-Pro)]₂(Oxa), using a very accessible, simple and efficient methodology for α-aminophosphonate synthesis using an aromatic aldehyde, an aromatic amine and diphenyl phosphite. This procedure was developed using a low catalyst loading of cerium(iii) prolinate and it has allowed for the recycling of the catalyst.

Full text of DOI:10.1039/c5ra27064b

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: C. D. G. da Silva,
A. R. Oliveira, M. P. D. Rocha, R. Katla, E. Botero, É. C. da Silva and N. L. C. Domingues, RSC Adv., 2016,
DOI: 10.1039/C5RA27064B.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Please do not adjust margins
Page 1 of 7
RSC Advances
View Article Online
DOI: 10.1039/C5RA27064B
Journal Name
ARTICLE
A new, efficient and recyclable [Ce(L-Pro)]2(Oxa) as a
heterogeneous catalyst used in Kabachnik-Fields reaction
Caren D. G. da Silva,a Aline R. Oliveira,a Mariana P. D. Rocha,a Ramesh Katla,a Eriton Rodrigo
Botero,b Érica C. da Silva,c and Nelson Luís C. Dominguesa
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Herein we introduce a new catalyst for the Kabachnik-Fields reaction, the [Ce(L-Pro)]2(Oxa), in a very accessible, simple
and efficient methodology for α-aminophosphonates synthesis using some aromatic aldehyde, aromatic amine and
diphenyl phosphite. This procedure was developed inserting a low catalytic loading of cerium (III) prolinate and it has
www.rsc.org/
allowed
the
recycle
of
the
catalyst.
many types of phosphorus reagent, methodology that apply a
reusable catalyst, mainly the less reactive such as aryl phosphites,
Introduction
using
the
one-pot
methodology
has
become
Organophosphorus compounds are useful building blocks for their
medicinal applications. Among them, the aminophosphonic acids
are one class of organic compounds that had attracted the
attention of many researches groups around the world because
frequently this class has presented some biological properties such
as antibacterial, antithrombotic agent, anti-inflammatory agent,
carcinogenic drugs, pesticides and HIV protease.1-2 Besides, the
necessary.9-10 It is observed that lanthanides have greater effects on
the α-aminophosphonates reaction.11 The first example using
lanthanides complexes for the synthesis of α-aminophosphonates
was described by Shibasaki12 et al. by using lanthanum-potassium-
BINOL, however, unfortunately, the authors described the use of
high load of the catalyst (5-20 % mol). Furthermore, it is widely
known that lanthanoids complexes used as catalysts represents an
efficient method to produce high yields and high enantiomeric
excess in reactions of α-aminophosphonates.13 For these reasons, it
is important to develop a new, efficient and green catalyst which
may be inserted on the Kabachnik-Fields reaction. Our research
group have worked with the application of some hybrid
heterogeneous catalyst in many organic reactions e.g. thio-Michael
reaction but all the catalyst had a zinc metal.14 In order to modify
the catalyst we preconize herein a oxalate cerate (III) - N,O (L)-
synthesis of aminophosphonic derivatives has received
a
considerable importance due to their structural analogy to the
aminoacids.3 For this reason, several methodologies have been
developed aiming the synthesis of α-aminophosphonates. Among
them, Kabachnik-Fields reaction is one of the easiest and most
direct approaches, for being carried out using aldehyde, amine and
diphenyl phosphite.4 Usually, this reaction could be catalysed by
Lewis acids, such as, SnCl2, SnCl4, ZnCl2 and MgBr2, but these
reactions cannot be done as one-pot.5 Among many synthetic
approaches of the α-aminophosphonates synthesis, the nucleophilic
addition of phosphites to imines is the most useful method.
However, many imines are hygroscopic and are not stable for
isolation.6 Moreover, this procedure usually presents long reaction
times, difficult procedures, low yields, the use of stoichiometric
amounts of catalyst, difficulties of separation and the recycling and
generally only dialkyl phosphite is used as phosphorus reagents.7-8
Due to the biological potential of the α-aminophosphonates, the
development of a new and simple method that enables the use of
prolinate or [Ce(L-Pro)]2(Oxa) (Figure 1), as
a heterogeneous
catalyst in Kabachnik-Fields reaction. In other words, herein, we
report an eco-friendly, easy and efficient methodology for the
synthesis of α-aminophosphonates using [Ce(L-Pro)]2(Oxa) catalyst.
This catalyst can be separated by filtration and can be reused other
times in the reaction and it is almost insoluble in any solvent.
O
O
NH
Oxalate
Ce
O
NH
O
2
Figure 1. Purposed structure for [Ce(L-Pro)]2(Oxa).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 2 of 7
View Article Online
DOI: 10.1039/C5RA27064B
ARTICLE
Journal Name
Experimental Section
General methods:
All chemical reagents and solvents without any specific treatment.
The respective reactions were monitored by Thin Layer
Chromatography (TLC) MACHEREY-NAGEL (SIL G / UV254). The
purification of the compounds was performed by recrystallization
solvent using Chloroform / Hexane to 65°C. 1H and 13C NMR spectra
were recorded in CDCl3 on Bruker (300 MHz and 75 MHz
respectively) spectrometer. The infrared spectra were recorded on
FT/IR 4100 type A spectrometer of Jasco.
Figure 2. IR for Ce[(L-Pro)2(Oxa)] in KBr spectroscopic.
observe that even proline and sodium oxalate are very well
crystallized, and this diffraction peaks can be indexed as the
references, respectively.13 The starting materials and the catalyst
presented a different pattern on X-ray diffraction, what indicated
the successful of the synthesis. Besides, by the analysis of literature
for a similar compound containing cerium and a different amino
acid in the structure, we observed that the X-ray data were very
similar.15
Preparation of catalyst:
[Ce(L-Pro)]2(Oxa) was synthesized using proline (2.7 mmol) in
methanol (15 mL) and aqueous sodium hydroxide solution (2.7
mmol in 1mL) at room temperature for 10 minutes. After that, it
was added cerium (III) cloride (1.4 mmol), the reaction crude was
stirred by 45 minutes and it was added few drops of sodium oxalate
solution (0.1g/mL) as precipitate agent. The semi-solid was
centrifuged, washed with methanol and dried overnight at 40 °C
and a pale yellow semi-solid was obtained.
1,0
a)
0,8
0,6
0,4
0,2
0,0
General procedure for the preparation of α-aminophosphonates:
Aldehyde (2.2 mmol), aniline (2 mmol), diphenylphosphite (2 mmol)
and [Ce(L-Pro)]2(Oxa) catalyst (1 mol %) were added to magnetic
stirrer in toluene (10 mL) at room temperature. The progress of the
reaction was monitored by TLC (eluent: EtOAc/hexane, 10:90). After
the reaction was completed the catalyst was separated by filtration.
0
500
1000
1500
2000
2500
After the product was purified by recrystallization
(chloroform/hexane) the α-aminophosphonates were obtained.
0,8
0,6
0,4
0,2
0,0
-0,2
b)
Results and Discussion
First of all, we performed the synthesis of the catalyst using the
same procedure described by Darben14 here using a cerium salt
(CeCl3.H2O) (see ESI for more information about the synthesis).
After the reaction the semi-solid was analysed by FTIR and DRX and
the data are presented on Figure 2 and 3 respectively.
By the analysis of the FTIR, we observed that for the νC=O for
[Ce(L-Pro)]2(Oxa) was shifted to a higher frequency (1636 cm-1)
which indicated that oxygen sp3 was bonded to the cerium atom
and this interaction increased the bond order on the carbonyl
group. Furthermore, we observed the decreasing to of frequency
for νC-O in cerium complex (from 1380 for proline to 1322 cm-1 for
[Ce(L-Pro)]2(Oxa) which indicated the same interaction previously
described. At the end, we observed that the band at 780 cm-1
indicated the interaction between nitrogen and cerium. It is worth
mentioning that the band at 3427 cm-1 is due to the presence of
water in the catalyst’s structure. All these results are in
concordance with literature data for similar compounds containing
cerium13. We also performed the X-Ray diffraction patterns by the
analysis of all the starting materials and the [Ce(L-Pro)]2(Oxa) and
the data are presented at Figure 3. The results enabled us to
0
500
1000
1500
2000
2500
1,0
0,8
0,6
0,4
0,2
0,0
c)
0
500
1000
1500
2000
2500
Figure continued….
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 3 of 7
View Article Online
DOI: 10.1039/C5RA27064B
Journal Name
ARTICLE
0,8
Table 2. Examine the catalyst loadings for Kabchnik-Fieldsreaction
using [Ce(L-Pro)]2(Oxa) as a catalyst
d)
0,6
Catalyst loading (% mol)
Yield (%)b
0,4
0,2
0,0
c
0
1
2
96
97
-0,2
[a] Reaction conditions: benzaldehyde (2.2 mmol), aniline (2.0 mmol) and
diphneylphosphite (2.0 mmol) at room temperature [b] Yields by recrystallization. [c]
No reaction.
0
500
1000
1500
2000
2500
Figure 3. X-Ray diffraction patterns of proline (a), cerium chloride
(b), sodium oxalate (c) and [Ce(L-Pro)]2(Oxa) (d).
using various substituted benzaldehydes, substituted anilines, and
diphenyl phosphite (Table 3). Concerned to benzaldehydes
derivatives, we observed that the withdrawing groups bonded at
para-position furnished the α-aminophosphonates in shorter
reaction time whereas the donors groups furnished them in long
ones, what was expected because the withdraw groups confers to
the carbonyl carbon lower electronic density and it makes the
After these analysis, we inserted the [Ce(L-Pro)]2(Oxa) on the
Kabachnik-Fields reaction aiming to identify the optimum catalytic
system. So, we carried out the standard reaction using aniline,
benzaldehyde and diphenyl phosphite and [Ce(L-Pro)]2(Oxa) in
different solvents using the methodology described by Zhu and co-
workers.11 As shown in Table 1, the solvent have interfered directly
over the yields. Moreover, we observed that the [Ce(L-Pro)]2(Oxa)
was compatible with many low polarity solvents. Thus, we carbonyl group more reactive (more electrophilic) when compared
established toluene as the best solvent of this reaction (96% of
yield).
to the donor ones. So, the imine will be obtained quickly in such
cases and also, and consequently, the α-aminophosphonates. This
can be confirmed by the analysis of both entries 2 and 8 (nitro
substituted), in which the change of the position of nitro group
from para- to meta- increased twice the reaction time. Regarding
to anilines derivatives, we observed that donors group bonded at
the para-position (entries 18 – 20), contrary to what we expected,
have produced the α-aminophosphonate in higher reaction time
than anilines containing withdraw groups at para-position (entries
13 – 17).
Table 1. Optimization of the synthesis of α-aminophosphonates.
Solvent
Time
Yield[b]
As observed on the purposed mechanism, we concluded, with
respect to cycle #1, that the catalyst affected this cycle making this
step faster. We determine this when we used [Ce(L-Pro)]2(Oxa) as
catalyst in the imine reactions. In this case, the catalyst accelerated
the reaction affording the imine in a lower reaction time when
compared to data described in literature. For the second cycle, the
catalyst affected the reaction by increasing the positive charge on
the imine carbon as described in intermediate #8.
Toluene
DCM
CH3CN
THF
10
10
10
60
96
90
55
80
No solvent
60
0
[a] Reaction conditions: benzaldehyde (2.2 mmol), aniline (2.0 mmol) and diphenyl
phosphite (2.0 mmol) and 1 % mol catalyst at room temperature. [b] Yield of isolated
product.
So, the strong withdrawing groups (NO2 and F) will difficult this
interaction higher than the moderate groups (Cl, Br and I) but both
will activate the C=N. On the other hand, donors groups, despite
the fact they decrease the electronic potential of nitrogen lone pair
(more basic), they will not increase the eletrophilicity of carbonyl
carbon in comparison to the previous ones (NO2, F, Cl, Br and I). For
this reason, for withdraw groups, the Kabachnik-Fields reactions
using [Ce(L-Pro)]2(Oxa) will be carried out at lower times than the
ones with electron donors groups. We also performed the recycling
of the catalyst for the reactions using para-anisaldehyde, aniline
and diphenyl phosphite (entry 6, Table 2 - see procedure in ESI). By
the analysis of the data, we concluded that the catalyst efficiency
was decreased every reuse (Table 4 entries 1-3). But as described
herein for this process using only 1% mol of the catalyst, its
reusability did not depreciate this methodology.
Grate news related to the reaction time also surprised us. Zhu11
described the Kabachnik-Fields reactions using a diethyl phosphite
(a better nucleophile than diphenyl phosphite used by us) in 6h and
our procedure has spent only 10 minutes (Table 1).We also studied
the effect of catalyst load over yields of the standard reaction
(Table 2). We observed that the best catalyst loading was 1 % mol
(96% of yield). However, the reaction did not afford any product
without catalyst (blank reaction). Furthermore, the increase of the
catalyst loading did not furnished a substantial increase of the
yields. Besides, we did not observe any sub-product as Pudovik
reaction. After establishing all the general procedures for
Kabachnik-Fields reaction using [Ce(L-Pro)]2(Oxa) as
a
heterogeneous catalyst, we extended the same protocol for several
other reactions aiming to obtain some α-aminophosphonates by
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 4 of 7
View Article Online
DOI: 10.1039/C5RA27064B
ARTICLE
Journal Name
Table 3. Kabachnik-Fields reactions using [Ce(L-Pro)]2(Oxa) as a
Amine
NH2
Time (min)
Yielda (%)
Aldehyde
CHO
Product
Entry
13
catalyst.
O
OPh
H
N
P
Yielda (%)
Entry
1
Aldehyde
CHO
Amine
NH2
Product
Time (min)
OPh
20
91
O2N
O
O
OPh
OPh
H
N
NO2
NH2
P
P
10
96
O
H
OPh
CHO
N
P
OPh
5
5
96
96
14
15
CHO
OPh
OPh
H
N
Cl
NH2
Cl
2
10
99
96
93
NH2
CHO
O
OPh
H
NO2
N
P
OPh
NO2
Br
CHO
O
P
OPh
OPh
Br
H
N
NH2
3
10
NH2
CHO
CHO
CHO
O
OPh
H
N
P
P
Cl
16
17
18
20
OPh
96
89
89
Cl
F
F
CHO
O
OPh
H
NH2
N
P
OPh
NH2
10
4
O
OPh
OPh
H
N
5
F
I
F
I
O
OPh
CHO
H
NH2
N
P
NH2
OPh
O
OPh
H
91
5
10
60
N
P
50
OPh
Br
MeO
OMe
NH2
Br
CHO
O
OPh
H
NH2
N
P
CHO
CHO
O
OPh
H
OPh
N
P
6
94
60
60
OPh
99
98
19
Me
OMe
CHO
Me
OMe
OPh
NH2
O
OPh
O
H
H
NH2
N
P
N
P
OPh
OPh
20
7
94
60
Me
Me
a.
Yields by recrystallization
CHO
O
OPh
NH2
H
N
P
OPh
8
97
20
Aiming to analyse the catalyst’s structure and trying to obtain some
information able to confirm what is responsible for the decreasing
of the yields in sequential catalysis cycles, we performed the SEM
and EDS for the catalyst before and after the reaction (Figure 4).
The data indicated that there were no changes neither on the
morphology nor on the atomic percentage. Besides, we observed
that there was a few loss of the catalyst loading per cycle (around
18%).
NO2
NO2
CHO
O
OPh
OPh
H
N
NH2
P
9
96
5
N
N
CHO
O
OPh
OPh
H
N
NH2
P
10
89
20
Table 4. Kabachnik-Fields reactions using [Ce(L-Pro)]2(Oxa)
CF3
recyclability.
CF3
O
Yielda
(%)
NH2
Cycle
ꢀ
Yield
(per cycle)
OPh
OPh
H
N
P
11
98
60
20
CHO
S
#1
#2
#3
94
80
65
-
S
14
15
O
NH2
OPh
H
96
CHO
N
P
OPh
12
a. Yields by recrystallization.
Table continued…
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 5 of 7
RSC Advances
View Article Online
DOI: 10.1039/C5RA27064B
Journal Name
A1
ARTICLE
A2
B1
B2
Atom Percentage
Atom Percentage
A3
O
C
27.53
3.67
O
C
30.73
1.47
Na
Ce
Cl
11.27
52.87
4.63
Na
Ce
9.60
58.13
Figure 4. SEM and EDS for [Ce(L-Pro)]2(Oxa) before the reaction (A1, A2 and A3) and after the reaction (B1, B2 and B3).
O
O
Ph
H
O
N
Ce
H
O
O
HN
O
O
O
HN
O
Ph
Ce
Ph
O
O
N
NH
O
-H+ shift
O
N
H
2
1
Ph
N
Ph
-H+
Ph
Cycle #2
O
N
= Proline group
8
Ce
3
Ph
O
O
H
O
O
PH
PhO
PhO
O
Ce
7
NH
O
Cycle #1
Ph
O
O
N
H
NH
Ph
4
N
N
Ph
+H+
Ce
9
Ph
Ph
HO
O
OPh
OPh
H
P
O
Ce
N
6
O
O
Ph
H2N
Ph
O
NH
Ph
OPh
OPh
H
N
O
Ce
Ph
P
N
Ph
NH2
Ph
Ph
10
OH
5
Scheme 1. Proposed mechanism of the Kabacnick-Fields reaction catalyzed by [Ce(L-Pro)]2(Oxa).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 6 of 7
View Article Online
DOI: 10.1039/C5RA27064B
ARTICLE
Journal Name
Therefore, as we carried out the next cycles in the same flask and
without any further catalyst charge and maintaining the same
starting materials amount used on the first cycle, we can assign that
this loss is strongly associated with the decrease of the subsequent
reaction yields.
8. (a) H. Ghafuri, A. Rashidizadeha, H. R. E. Zanda, RSC Adv.
2016, 00, 1. (b) E. Mollashahi, H. Gholami, M. Kangani, M.
T. Maghsoodlou, Heteroat. Chem., 2015, 0, 1.
9. F. Xu, Y. Luo, J. Wu, W. Shen, H. Chen, Heteroat. Chem.,
2006, 17, 389.
10. S. Sobhani, Z. M. Falatooni, M. Honarmand, RSC Adv.,
2014, 4, 15797.
Conclusions
11. 9 M. Shibasaki, N. Yoshikawa, Chem. Rev., 2002, 102,
We have successfully developed a new versatile catalyst, the [Ce(L-
Pro)]2(Oxa), in Kabachnik-Fields reaction which have afforded high
yields of α-aminophosphonates by the use of a very accessible,
simple and efficient methodology of minimal of catalyst loading in
short reaction time. In relation to its reusability, it was possible only
in some cycles but this does not depreciate this procedure.
2187.
12. M. Shibasaki, H, Gröger, in Lanthanides: Chemistry and
Use in Organic Synthesis (Ed.: S. Kobayashi), Springer,
Heidelberg, 1999, 199 and references inside there.
13. X. Zhu, S. Wang, S. Zhou, Y. Wei, L. Zhang, F. Wang, Z.
Feng, L. Guo, X. Mu. Inorg. Chem., 2012, 51, 7134.
14. M. P. Darben, A. R. Oliveira, C. R. Winck, A. W. Rinaldi, N.
Acknowledgements
L. C. Domingues, Tetrahedron Lett., 2014, 55, 4123.
The author (N. L. C. D. and C. D. G. S) thank to Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq/Brazil) for financial
support (Process: 314140/2014-0 and 400706/2014-8 CNPq -
Brazil) and scholarship. The authors (N. L. C. D. and M. P. D. R) thank
to Fundação de Apoio ao Desenvolvimento do Ensino, Ciência e
Tecnologia do Estado de Mato Grosso do Sul (FUNDECT/Brazil) for
15. (a) S. Myung, M. Pink, M. H. Baik, D. E. Clemmer, Acta
Cryst. 2005, 61, o506-o508. (b) D. A. Reed, M. M.
Olmstead, Acta Cryst. 1981. B37, 938.
16. B. Ptaszyński, A. Zwolińska, Polish J. Environ. Studies,
2001, 10 (4) 257.
financial
suport
and
fellowship
(Processo
Chamada
FUNDECT/CAPES n° 02/2014 – Mestrado em Mato Grosso do Sul)
Furthermore, the author (A. R. O) thanks to Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior (CAPES/Brazil) for
her scholarships.
Notes and references
Keywords: cerium • aminophosphonates • heterogeneous catalysis
• proline
1. (a) R. Ghosh, S. Maiti, A. Chakraborty, D. K. Maitil, J. Mol.
Catal., 2003, 210, 53. (b) P. A. Bartlett, J. E. Hanson, P. P.
Giannousis, J. Org. Chem., 1990, 55, 6268. (c) P. Kafarski,
B. Lejczak, Phosphorus Sulfur Silicon Relat. Elem. 1991, 63,
1993. (d) M.C. Allen, W. Fuhrer, B. Tuck, R. Wade, J.M.
Wood, J. Med.Chem., 1989, 32, 1652. (e) E. W. Logusch,
D.M. Walker, J.F. McDonald, G.C. Leo, J. E. Franz, J. Org.
Chem., 1988, 53, 4069. (f) A. Peyman, K.-H. Budt, J.
Spanig, B. Stowasser, D. Ruppert, Tetrahedron Lett., 1992,
33, 4549. (g) A. Peyman, W. Stahl, K. Wagner, D. Ruppert,
K.-H. Budt, Bioorg. Med. Chem. Lett., 1994, 4, 2601.
2. Z. Rashid, H. Naieimi, R. Ghahremanzadeh, RSC Adv.,
2015, 5, 99148.
3. Y. Zhanga, C. Zhu, Catal. Commun., 2012, 28, 134.
4. S. Rostamniaa, H. Xin. J. Mol. Liq. 2014, 195, 30.
5. S. Sobhania, E. Safaeib, M. Asadic, F. Jalilia. J. Org. Chem.,
2008, 693, 3313.
6. M. H. Sarvari. Tetrahedron, 2008, 64, 5443.
7. V. H. Tillu, D. K. Dumbreb, R. D. Wakharkara, V. I.
Choudhary. Tetrahedron Lett., 2011, 52, 863.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 7
RSC Advances
View Article Online
DOI: 10.1039/C5RA27064B
Graphical Abstract